The adrenal glands secrete steroid hormones such as cortisol which are essential to life. Victims of Addison's disease suffer from lymphocytic infiltration and the subsequent destruction of these important glands. The initial symptoms of Addison's disease are subtle, consisting of such features as muscular weakness and increased pigmentation of the skin. As the disease progresses, unexplained dehydration, low blood pressure, and disturbances in blood electrolytes become manifest. Once the adrenal glands fail completely, life is not possible without specific hormone replacement treatment. However, if the disease is correctly diagnosed, the affected patient can live a normal life by taking replacement quantities of steroid hormones most usually as daily pills. Family members of patients with Addison's disease are also prone to the disease. Since the treatment of this otherwise fatal disease can so readily restore health and bodily functions, the identification of patients or their family members with impending disease is important to the appropriate treatment of the condition.
Addison's disease is probably much more common than the limited number of prevalence studies available would suggest. The most famous American with the disease was the late President John F. Kennedy, albeit his affliction was a well-kept secret for most of his life. He was diagnosed after a classical presentation of the disease at age 30, while he was returning through London from a visit to Ireland, only one year after being elected to the U.S. House of Representatives. Within three years he was established on steroid replacement therapies of 25 mg of cortisone and the intermittent implantation of 150 mg DOCA pellets. Throughout the years, his appearance changed dramatically from a gaunt congressman with Addison's disease to that of a heavy set and jowly senator and president on steroid therapy. As a senator, he successfully underwent back surgery after his diagnosis of adrenocortical failure in 1955, an event which was published in JAMA Archive of Surgery although he was not identified as the patient until a follow-up article in JAMA in 1967 (Blair, Jr., C., J. Blair [1976] The Search for JFK, Berkley Publishing Corp., New York, pp. 560-579).
There are many causes of Addison's disease; however, two of the most important are tuberculosis infections and autoimmunity. The treatment for Addison's disease depends upon the cause. Tuberculosis-generated Addison's disease is treated by chemotherapy to eliminate the microorganism. In the case of autoimmune Addison's, however, it is the host's own immune system that destroys the host's adrenal gland. Therefore, treatment of this form of the disease can involve immunomodulation.
In autoimmune Addison's disease, there is loss of cells of the adrenal cortex but not of the medulla. The adrenal cortex is arranged anatomically into 3 zones, each with distinct, albeit overlapping, properties and functions. Adjacent to the fibrous capsule is found the zona glomerulosa, characterized by nests of cells involved in the secretion of steroid hormones that promote sodium retention and potassium excretion. The most powerful of these hormones is aldosterone. Moving into the gland, the zona faciculata is next encountered. Here, columns of epithelial cells secrete quantities of the glucocorticoid hormones, principally cortisol. Glucocorticoid hormones have powerful metabolic action promoting breakdown of body protein stores and enhancing hepatic gluconeogenesis, thus raising blood glucose levels when found in excess. The innermost zone has cells distributed in a reticular pattern which secrete the 17-hydroxylated sex hormones, principally dihydro-epiandrosterone. All three zones become destroyed by the disease. The adrenal medulla is spared in autoimmune Addison's disease and is an organ for the production and secretion of catecholamines.
Autoimmune Addison's disease often occurs together with other autoimmune endocrinopathies. This phenomenon has been termed autoimmune polyglandular disease or APS (Neufeld et al. [1981] Medicine 60:718-723). In type 1 APS, patients are often affected by several component problems, including hypoparathyroidism, hypogonadism, pernicious anemia, and chronic active hepatitis. Patients also often have underlying defects in cellular immunity leading to chronic muco-cutaneous moniliasis. In the more common APS, type 2, Addison's disease is associated with chronic lymphocytic thyroiditis (Hashimoto's disease, but sometimes Graves' disease), insulin dependent diabetes (IDD), and pernicious anemia. In type 1 APS there are no genetic associations with human leukocyte antigens (HLA); however, predisposition to type 2 disease is strongly linked to the HLD-DR locus, and particularly to the DR3 and DR4 alleles (Maclaren et al. [1986] J. Clin. Endo. Metab. 62:455-459). Addison's disease occurring in both contexts is associated with circulating autoantibodies to the adrenal cortex, which are detectable by indirect immunofluorescence of sections of frozen human adrenal glands.
The adrenocortical autoantibodies of the disease sometimes react to steroid hormone secreting cells in non-adrenal sites such as the granulosa/luteal portion of the graafian follicles of the ovary, the Leydig cells of the testes, and the syncytiotrophoblast of the placenta. Therefore, some patients can have both the common adrenal gland-specific antibody as well as the steroidal cell autoantibody (Elder and Maclaren [1981] J. Clin. Endocrinol. Metab. 52:143-148). These patients are only those patients afflicted with type 1 APS. Patients with type 2 APS only have adrenal specific antibodies.
Recently, several papers have reported serum reactivity to p450 enzymes in patients with type 1 APS. One paper describes reactivity with the 17-hydroxylase enzyme (Krohn et al. [1992] Lancet 339:770-773); the others describe reactivity to the 21-hydroxylase enzyme (Winquist et al. [1992] Lancet 339:1559-1562; Bednarek et al. [1992] FEBS Lett. (Netherlands) 309:(1):51-55). These two enzymes are important to steroidogenesis. Each enzyme is 55 kDa. Neither of these enzymes are targeted by other autoimmune endocrinopathies.
The enzyme 21-hydroxylase promotes the conversion of pregnenalone to progesterone in the chemical pathways for steroid hormone formation. The enzyme has been described in U.K. Patent Application GB 2 256 046 for use in methods and kits for detecting adrenal autoantibodies. Others have suggested inconsistency of results in using various immunological tests for the detection of Addison's disease (Freeman, M., P. Weetman [1992] Clin. Exp. Immunol. 88(2):275-279). At present, diagnosis and therapy surveillance of Addison's disease are carried out by the nonspecific rapid adrenocorticotropin hormone (ACTH) test (Oelkers et al. [1992] J. Clin. Endocrinol. Metab. 75(1):259-264; Davenport et al. [1991] Am. Faro. Physician 43(4):1338-1342).